ABSTRACT Alzheimer?s disease (AD) is the most common form of adult-onset dementia and the number of patients with AD escalates dramatically each year. AD patients display hippocampal atrophy, memory impairment, and other cognitive and olfactory deficits. On the other hand, new neurons are generated throughout adulthood in two regions of the brain, the dentate gyrus of the hippocampus and the sub- ventricular zone of the olfactory bulb and are incorporated into hippocampal network circuitry. In adults, the annual turnover of stem cells into neurons is 1.75% with a modest decline during aging. By contrast, the estimated annualized hippocampal atrophy rate is 1.41% per year for cognitively normal older people and 4.66% for patients with AD pathology. Disruption of this process has been postulated to contribute to neurodegenerative diseases including AD. Alterations in hippocampal neurogenesis in AD could either provide protection by proliferation of neural progenitor cells or cause accelerated neural degeneration due to impairment of neuronal network and synaptic plasticity. Many of the molecular players in AD are also modulators of adult neurogenesis, but genetic mechanism underlying adult neurogenesis in AD is still unclear. Recently, we discussed potential modulators of adult neurogenesis and their roles in neurodegenerative diseases in a review paper. The overall goal of the proposed project is to identify candidate genes and pathways which play a role in neurogenesis in adult brain and to test our hypothesis that 1) the neurogenesis pathway is significantly associated with hippocampal volume and 2) hippocampal neurogenesis-related genes and pathways are significantly perturbed in AD. We will use a large-scale imaging genetics meta-analysis summary and multimodal neuroimaging (MRI, PET) and genome-wide genotyping data from several independent cohorts. The specific Aims: (1) identify candidate genes associated with hippocampal neurogenesis using a pathway-based systems biology approach from publicly available databases and literature mining; (2) perform genome-wide gene-set enrichment analysis for hippocampal volume using a large-scale neuroimaging genetics meta-analysis (N~15,000); and (3) perform a neurogenesis-related targeted gene-based and pathway-based association analysis using AD-related biomarker endophenotypes. The proposed project will enable discovery of new genetic contributions to hippocampal neurogenesis and has strong translational potential to identify novel therapeutic targets related to learning and memory and AD neuroprotection. RELEVANCE TO PUBLIC HEALTH AD is a progressive neurodegenerative condition with no validated disease modifying treatment. The fight against AD has increasingly become a top national priority. Identifying neurogenesis-related genes associated with AD provides valuable insights into the molecular mechanisms of AD and helps to identify new therapeutic strategies.